CN111407882A - Methods and compositions of neuregulin for preventing, treating, or delaying heart failure with preserved ejection fraction - Google Patents

Abstract

The present invention relates to the use of Nurengulin protein in the preparation of a medicament for preventing, treating or delaying heart failure with preserved ejection fraction in mammals, and the said use for preventing, treating or delaying heart failure with preserved ejection fraction in mammals method of using the drug. In particular, the present invention provides a method of preventing, treating or delaying heart failure with preserved ejection fraction in mammals in a particular population having or at risk for heart failure with preserved ejection fraction Drugs that contain Nergylin protein are used in In particular, the present invention relates to a novel indication of neuregulin in the treatment of cardiovascular disease in heart failure with preserved ejection fraction.

Description

Neuregulin for the prevention, treatment or delay of heart failure with preserved ejection fraction Methods and compositions for exhaustion

technical field

The present invention relates to the use of Nurengulin protein in the preparation of a medicament for preventing, treating or delaying heart failure with preserved ejection fraction in mammals, and the said use for preventing, treating or delaying heart failure with preserved ejection fraction in mammals method of using the drug. In particular, the present invention provides a method of preventing, treating or delaying heart failure with preserved ejection fraction in mammals in a particular population having or at risk for heart failure with preserved ejection fraction Drugs that contain Nergylin protein are used in In particular, the present invention relates to a novel indication of neuregulin in the treatment of cardiovascular disease in heart failure with preserved ejection fraction.

Background of the Invention

Neuregulin (neuregulin, NRG; heregulin, HRG), also known as glial growth factor (GGF), neu differentiation factor (new differentiation factor, NDF), is a glycoprotein with a molecular weight of about 44KD. It is a ligand of the ErbB family of tyrosine kinase receptors. The neuregulin family contains 4 members: NRG1, NRG2, NRG3, NRG4 (Falls et al., Exp Cell Res. 284:14-30, 2003). NRG1 plays an important role in the nervous system, heart, and breast, and there is also evidence that NRG1 signaling plays a role in the development, function, and pathogenesis of human diseases, including schizophrenia and breast cancer, in several other organ systems. There are many isoforms of NRG1. Studies on mutant mice (knockout mice) have shown that different isoforms in the N-terminal region or epidermal growth factor (EGF)-like region have different functions in vivo. The present invention is based on neuregulin 1β (NRG1β).

Neuregulin 1β is a transmembrane protein (Holmes et al., Science 256, 1205-1210, 1992). The extra-membrane part is N-terminal, including the immunoglobulin-like domain (Ig-like domain) and the EGF-like domain (EGF-like domain), and the intra-membrane part is C-terminal. Under the action of metalloproteinases in the extracellular matrix, the extramembrane part of neuregulin can be cleaved off by enzymes and become free, which is favorable for binding with ErbB receptors on the surface of surrounding cells and activating corresponding cell signaling.

The ErbB receptor family is also divided into four categories, ErbB1, ErbB2, ErbB3 and ErbB4, all of which are transmembrane proteins with molecular weights around 180-185KD. Except for ErbB2, they all contain ligand-binding domains at the N-terminus outside the membrane; except for ErbB3, they all contain protein tyrosine kinase activity at the C-terminus in the membrane. Among them, ErbB1 is a receptor for epidermal growth factor, and ErbB3 and ErbB4 are receptors for neuregulin. Among the receptors for neuregulin, only ErbB2 and ErbB4 are highly expressed in the heart (Yarden et al., Nat Rev Mol Cell Biol, 2:127-137, 2001).

When neuregulin binds to the extramembrane portion of ErbB3 or ErbB4, it causes ErbB3, ErbB4 to form heterodimers with other ErbB receptors (often including ErbB2), or ErbB4 itself to form homodimers, which then leads to receptor The intramembrane portion of the body is phosphorylated (Yarden et al., Nat Rev Mol Cell Biol, 2:127-137, 2001). The phosphorylated intramembrane portion can further bind to various signaling proteins in the cell, thereby activating the downstream ERK or AKT signaling pathway, causing a series of cellular responses: including stimulation or inhibition of cell proliferation, apoptosis, cell migration, cell differentiation or cell adhesion.

Neuregulins are particularly important for the development of the heart (WO0037095, CN1276381, WO03099300, WO9426298, US6444642, WO9918976, WO0064400, Zhao et al., J. Biol. Chem. 273, 10261-10269, 1998). In early embryonic development, the expression of neuregulin is mainly confined to the endocardium, and is subsequently released to the surrounding cardiomyocytes via the paracrine pathway and binds to the extramembrane portion of the protein tyrosine kinase receptor ErbB4 on the cell membrane, which in turn forms with ErbB2 heterodimers. Formation and activation of the ErbB4/ErbB2 complex is required for early spongy heart trabeculae formation. Deletion of any of the three protein genes for neuregulin, ErbB4 and ErbB2, renders embryos devoid of trabeculae and dies in the uterus early in development. WO0037095 shows that a certain concentration of neuregulin can continuously activate the ERK signaling pathway, promote the growth and differentiation of cardiomyocytes, guide the reconstruction of the sarcomere and cytoskeleton at the adhesion of cardiomyocytes and cells, improve the structure of cardiomyocytes, and enhance the contraction of cardiomyocytes. WO0037095 and WO003099300 also indicate that neuregulin can be used to detect, diagnose and treat various cardiovascular diseases.

Some prior art documents related to the present invention are listed below: 1. Cardiac muscle function and manipulation: WO0037095; 2. New applications of growth factor neuregulin and its analogs: CN1276381; 3. Neuregulin based methods and composition for treating cardiovascular diseases : WO03099300; 4. Zhao YY, Sawyer DR, Baliga RR, Opel DJ, HanX, Marchionni MA and Kelly RA. Neuregulins Promote Survival and Growth of Cardiac Myocytes. J. Biol. Chem. 273, 10261-10269 (1998); 5. Methods for treating muscle diseases and disorders:WO9426298;6.Methods of increasing myotubeformation or survival or muscle cell mitogenesis,differentiation or survival using a neuregulin:US6444642.7.Therapeutic methods comprising use of aneuregulin:WO9918976;8.Methods for treating congestive heart failure: WO0064400; 9. Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, et al. Identification of heregulin, a specificactivator p185erbB2. Science 256, 1205-1210 (1992); 10. Falls DL. Neuregulins: functions, forms and signaling strategies. Experimental Cell Research, 284, 14-30 (2003). 11. Yarden Y, Sliwkowski X. Untanglin g the ErbB signaling Network. Nature Reviews: Molecular Cell Biology, 2127-137 (2001).

Heart failure (HF) is a syndrome of cardiac insufficiency caused by various heart diseases, including systolic heart failure (SHF) and diastolic heart failure (DHF). In 2008, the guidelines for the diagnosis and treatment of acute/chronic heart failure issued by the European Society of Cardiology (ESC) defined the latter as heart failure with preserved ejection fraction (HF-PEF). Systolic heart failure refers to the decrease of myocardial contractility, which makes cardiac output unable to meet the needs of body metabolism, insufficient blood perfusion of organs and tissues, and the performance of pulmonary circulation and/or systemic circulation congestion at the same time. Heart failure with preserved ejection fraction (HF-PEF), often referred to as diastolic heart failure, is caused by impaired left ventricular diastolic active relaxation capacity and reduced myocardial compliance, with increased myocardial stiffness due to hypertrophy of cardiomyocytes with interstitial fibrosis , resulting in impaired left ventricular filling during diastole, reduced stroke volume, and increased left ventricular end-diastolic pressure. In 2006, the epidemiological data of the American Heart and Lung Institute showed that heart failure with preserved ejection fraction or diastolic heart failure accounted for more than 50% of the total number of heart failure. Heart failure with preserved ejection fraction can exist alone or in combination with systolic dysfunction. Heart failure with preserved ejection fraction is more common in older women with hypertension, diabetes, and left ventricular hypertrophy.

Diastolic heart failure has similar symptoms and signs as systolic heart failure. Patients often have underlying diseases such as hypertension. The early manifestations of heart failure are unexplained fatigue, decreased exercise tolerance, and an increase in heart rate of 15 to 20 beats per minute, which may be an early sign of decreased left ventricular function. Then there may be exertional dyspnea, paroxysmal nocturnal dyspnea, high pillow sleep, etc. The patient may have abdominal or leg edema, and this is the primary or only symptom to see a doctor, and the patient's exercise tolerance impairment occurs gradually.

Diastole of the heart is a more complex physiological process than contraction involving many factors. Therefore, the diagnosis of heart failure with preserved ejection fraction or diastolic heart failure is more difficult than that of systolic heart failure. At present, the diagnosis can be made when the following conditions are met:

1. Have typical symptoms and signs of heart failure;

2. LVEF is normal (or slightly decreased by ≥45%), and the left ventricular morphology is normal;

3. There is evidence of basic heart disease, such as left ventricular hypertrophy and left atrial enlargement in hypertensive patients, and evidence of abnormal left ventricular diastolic function on echocardiography;

4. Increased BNP/NT-ProBNP;

5. No heart valve disease was found on echocardiography, and pericardial disease, hypertrophic cardiomyopathy, restrictive (infiltrating) cardiomyopathy, etc. were excluded.

The etiology of heart failure with preserved ejection fraction or diastolic heart failure is complex and diverse, and the left ventricular pressure/volume mechanism is a well-recognized one. In patients with hypertension, hypertrophic cardiomyopathy, and aortic valve stenosis, ventricular end-diastolic pressure is significantly increased, and left ventricular volume is significantly reduced, which affects ventricular filling, shifts the pressure-volume curve to the left, and forms concentric remodeling. Diastolic heart failure occurs due to long-term pressure overload.

Ventricular diastolic function (diastolic function) includes two stages of ventricular muscle relaxation (relaxation) (active energy consumption process) and compliance (compliance). Ventricular relaxation (relaxation) is the change of cardiac chamber pressure (dp/dt) per unit time during diastole, which is an active energy consumption process. Ventricular compliance (compliance) is the change in pressure (dp/dv) caused by the change in unit volume during diastole, which is a passive filling process. Relaxation is the active relaxation of ventricular myocardium in the early diastole, the ability of myocardial fibers to return to their pre-systolic length and pressure, and is an active energy-consuming process of energy-dependent Ca ²⁺ transport. It mainly includes isovolumic relaxation phase and early diastolic fast filling phase. Parameters reflecting left ventricular relaxation include: duration of isovolumic relaxation (IVRT), maximum rate of pressure drop (-dp/dt), mitral valve E-peak deceleration time (DT), etc. These parameters obtained by two-dimensional echocardiography and hemodynamic testing can evaluate the diastolic function of the heart to some extent.

In addition, heart failure with preserved ejection fraction also lacks specific treatment methods. The current treatment principles include the use of standard treatment drugs for improving symptoms of systolic heart failure such as blood pressure control, lowering ventricular rate, and diuresis to reduce fluid retention, such as vascular tension. β-blockers, diuretics, etc., but cannot improve the clinical symptoms and prognosis of heart failure with preserved ejection fraction. Finally, heart failure with preserved ejection fraction or diastolic heart failure has a poor prognosis, with slightly higher rates of patient readmissions and repeated hospitalizations, increasing the healthcare burden. The outcome of the development of diastolic heart failure is systolic heart failure. How to improve the diastolic performance of the heart in the early stage of diastolic heart failure and block its further deterioration is a great challenge facing the current treatment of diastolic heart failure.

There are no reports in the prior art literature of neuregulin for heart failure with preserved ejection fraction or diastolic heart failure. The present invention finds that administration of neuregulin to mammals can significantly improve the symptoms of heart failure with preserved ejection fraction, and can be used to prepare a medicament for preventing, treating or delaying heart failure with preserved ejection fraction in mammals.

SUMMARY OF THE INVENTION

A. SUMMARY OF THE INVENTION

The present invention is based on the scientific discovery that NRG is crucial to the development of the heart, and also plays a very important role in maintaining the function of the adult heart; based on the scientific discovery that NRG can strengthen the formation of myocardial cell sarcomere and cytoskeleton and intercellular connections; Based on the scientific discovery that NRG can improve cardiac function in animals or patients with heart failure in various animal models and clinical trials. NRG, NRG polypeptides, NRG mutants or other complexes with NRG-like functions are all within the scope of the present invention.

Neuregulin can bind to ErbB receptors on the surface of cardiomyocytes, continuously activate the ERK signaling pathway in cells, and change the structure of cardiomyocytes, thereby improving the function of cardiomyocytes.

A first aspect of the present invention provides a method of preventing, treating or delaying heart failure with preserved ejection fraction in mammals, especially humans. Including the administration of an effective amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof, or to increase NRG production and/or functional substances to prevent, treat or delay heart failure with preserved ejection fraction.

The second aspect of the present invention provides a pharmaceutical preparation for preventing, treating or delaying heart failure with preserved ejection fraction in mammals, especially in humans. The pharmaceutical preparation comprises an effective amount of NRG or a functional fragment thereof, or a nucleic acid encoding NRG or a functional fragment thereof, or a substance that increases the production and/or function of NRG, as well as pharmaceutically acceptable carriers, excipients, and the like. The pharmaceutical formulation can be used in combination with other drugs useful in the prevention, treatment or delay of heart failure with preserved ejection fraction.

Another aspect of the present invention provides a composition for preventing, treating or delaying heart failure with preserved ejection fraction in mammals, especially humans. The composition comprises the pharmaceutical preparation provided by the present invention for preventing, treating or delaying heart failure with preserved ejection fraction in mammals, and other medicines for preventing, treating or delaying heart failure with preserved ejection fraction.

The present invention also provides a kit for the prevention, treatment or delay of heart failure with preserved ejection fraction in mammals, especially humans, comprising one or more doses of the above-mentioned prevention, treatment or delay with preserved ejection fraction A pharmaceutical formulation or composition for heart failure, and instructions for how to use the pharmaceutical formulation or composition.

B. Definition

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as understood by one of ordinary skill in the art to which this invention belongs. All patent documents, patent application documents, published patent documents, and other publications are incorporated by reference. To the extent that the definitions set forth in this section are inconsistent with or contrary to the definitions set forth in the above references, the definitions set forth in this section shall control.

As used herein, "a" means "at least one" or "one or more than one" unless otherwise specified.

"Neuregulin" or "neuregulin" or "NRG" as used herein refers to a protein or polypeptide capable of binding and activating ErbB2, ErbB3, ErbB4 or a heterologous or homodimer thereof, including isoforms of neuregulin , EGF-like domains in neuregulins, polypeptides comprising neuregulin EGF-like domains, mutants or derivatives of neuregulins, and other neuregulin-like gene products capable of activating the aforementioned receptors. Neuregulin also includes NRG-1, NRG-2, NRG-3 and NRG-4 proteins, polypeptides, fragments and complexes with NRG-like functions. Preferably, the neuregulin is a protein or polypeptide that can bind and activate ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers. By way of example, but not by way of limitation, the neuregulin of the present invention is a fragment of the NRG-1β2 isoform, ie, a fragment of amino acids 177-237, which contains an EGF-like domain. The amino acid sequence of this fragment is: SHLVKCAEKEKTFCVNGGECFMVKDLSNPSRYLCKCPNEFTGDRCQNYVMASFYKAEELYQ (SEQ ID NO: 1). The neuregulin used in the present invention can activate the above-mentioned receptors and regulate their biological functions, such as stimulating skeletal muscle cells to synthesize acetylcholine receptors; promoting the differentiation, survival and DNA synthesis of cardiomyocytes. Neuregulin also includes those mutants of neuregulin that have conservative mutations that do not substantially affect biological function. It is well known to those of ordinary skill in the art that mutations of single amino acids in non-critical regions generally do not result in changes in the biological function of the protein or polypeptide (see Watson et al., Molecular Biology of the Gene, ^4th Edition, 1987, The Bejacmin/Cummings Pub.co., p. 224). The neuregulin used in the present invention can be isolated from natural sources, or obtained by recombinant technology, artificial synthesis or other means.

As used herein, "EGF-like domain" or "EGF-like domain" refers to a polypeptide fragment encoded by the neuregulin gene that can bind and activate ErbB2, ErbB3, ErbB4 or its heterologous or homodimer, and is associated with the following The EGF receptor binding regions described in the aforementioned references share structural similarity: WO 00/64400; Holmes et al., Science, 256: 1205-1210 (1992); US Pat. Nos. 5,530,109 and 5,716,930; Hijazi et al., Int. J. Oncol. , 13: 1061-1067 (1998); Chang et al, Nature, 387: 509-512 (1997); Carraway et al, Nature, 387: 512-516 (1997); Higashiyama et al, J. Biochem., 122: 675- 680 (1997); and WO 97/09425. In certain embodiments, the EGF-like domain binds and activates ErbB2/ErbB4 or ErbB2/ErbB3 heterodimers. In certain embodiments, the EGF-like domain comprises the receptor binding region amino acids of NRG-1. In certain embodiments, the EGF-like domain refers to amino acids 177-226, 177-237, or 177-240 of NRG-1. In certain embodiments, the EGF-like domain comprises the receptor binding region amino acids of NRG-2. In certain embodiments, the EGF-like domain comprises the receptor binding region amino acids of NRG-3. In certain embodiments, the EGF-like domain comprises the receptor binding region amino acids of NRG-4. In certain embodiments, the EGF-like domain comprises the amino acid sequence described in US Pat. No. 5,834,229: Ala Glu Lys Glu Lys ThrPhe Cys Val Asn Gly Gly Glu Cys Phe Met Val Lys Asp Leu Ser Asn Pro.

As used herein, "heart failure with preserved ejection fraction (HF-PEF)" is also referred to as heart failure with normal left ventricular ejection fraction (LVEF) (HFNEF), heart failure with preserved left ventricular ejection fraction (HF-PLVEF) ), heart failure with preserved systolic function (HF-PSF), diastolic heart failure (DHF), or diastolic heart failure, which is defined as normal or mildly decreased left ventricular ejection fraction (LVEF), primarily due to left ventricular diastolic It occurs due to impaired active relaxation ability and decreased myocardial compliance, and increased stiffness of cardiomyocytes with interstitial fibrosis, resulting in impaired left ventricular filling during diastole, decreased stroke volume, and increased left ventricular end-diastolic pressure. of heart failure. It can exist alone or in combination with systolic dysfunction.

As used herein, "isovolumic relaxation time (IVRT)" refers to a state of isovolumic closure in which the pressure of the ventricle continues to decrease, at which time the ventricle begins to relax and the aortic and atrioventricular valves are closed. IVRT is prolonged when left ventricular relaxation is impaired. When impaired LV relaxation improves, IVRT decreases.

As used herein, "rate of pressure drop (-dp/dt)" refers to the rate of drop in left ventricular pressure during isovolumic relaxation. The larger the value is, the faster the left ventricular pressure drops and the better the diastolic function of the heart, which is one of the reliability indicators for evaluating myocardial relaxation.

"Mitral valve E peak" as used here refers to the early diastolic peak (E) of the mitral valve of the heart, which reflects the maximum blood flow velocity through the valve during the rapid filling of the left ventricle, and the E peak of the mitral valve flow curve represents Active relaxation of the left ventricle in early diastole reflects left ventricular relaxation.

As used here, "E-peak descent time (DT)" refers to the mitral valve E-peak descending deceleration time, which is the deceleration time of blood flow formed by the movement of the mitral valve to the left atrium in the early diastole, reflecting the rapid filling of the left atrioventricular chamber. The pressure difference changes, and the smaller the value, the faster the pressure difference changes. Decreased active relaxation generally occurs in the early stage of the disease, and is manifested as a decrease in the early diastolic filling of the left ventricle, a decrease in the E peak, and a prolonged DT of >240ms.

As used herein, "other drugs for the treatment of heart failure with preserved ejection fraction" refers to drugs known to be useful in the treatment of heart failure with preserved ejection fraction, including angiotensin-converting enzyme inhibitors/angiotensin II receptors. β-blockers, calcium antagonists, cyclic adenosine monophosphate, catecholamines, nitrates, phosphatase inhibitors, diuretics, renin-angiotensin-aldosterone system (RAS) ) antagonists, myocardial energy optimizers, etc.

Detailed ways

Example 1: Study on the effect of recombinant human Nürngin on cardiac function in rats with hypertensive heart failure

To study the therapeutic effect of recombinant human Nürburgring (rhNRG) on the heart failure model of SHR hypertensive rats. METHODS: SHR hypertensive strain rats were used for normal feeding. During the feeding process, the heart function changes were monitored by central ultrasonography. At 16 months, the ejection fraction (EF) decreased to 70%, indicating that the heart failure model of hypertensive rats was successfully established. Rats with hypertensive heart failure were randomly divided into negative control group, NRG treatment group and captopril treatment group. rhNRG was continuously administered for 5 days and discontinued for 2 days as a treatment cycle. The NRG group received a total of 3 treatment cycles. treat. At the end of the second and third treatment cycles, echocardiography was performed on the rats in each group to determine the changes in cardiac function; .

1. Experimental animals

1.1 Strain and source: SHR hypertensive strain rats were purchased from the Animal Center of the Chinese Academy of Sciences. The WKY strain was used as a control for SHR and was also purchased from the Animal Center of the Chinese Academy of Sciences.

1.2 Gender and age: male, 6 weeks old.

1.3 Feeding: common rodent feed, free access to water, 12-hour light-dark cycle

2. Test drug

Specification: Neucardin ^TM , 61 amino acids, produced by Shanghai Zesheng Technology Development Co., Ltd.

3. Experimental materials

3.1 Cardiac Ultrasound: Philips Sonos 5500

3.2 Captopril: Sino-US Shanghai Bristol-Myers Squibb Pharmaceutical Co., Ltd.

4. Experimental method

4.1 Preparation of hypertensive heart failure rat model

SHR hypertensive strain rats were used, and they were fed normally. During the feeding process, the changes of cardiac function were monitored by central ultrasonography. After 16 months of feeding, the ejection fraction (EF) of SHR rats decreased to 70%, and the LVDd and LVDs increased significantly, indicating that the heart failure model of hypertensive rats was successfully established.

4.2 Grouping and Administration

After the model was successfully established, they were randomly divided into negative control group, NRG treatment group and captopril treatment group. rhNRG is administered by intravenous injection, the dose is 6.5ug/kg, once a day, continuous administration for 5 days and withdrawal for 2 days is a treatment cycle, and a total of 3 treatment cycles are received. At the same time, the NRG group was also given drinking water by gavage, twice a day; the administration method of captopril was gavage, the dose was 10 mg/kg, twice a day, continuous administration. At the same time, the NRG vehicle was administered by tail vein for 3 treatment cycles. The negative control group was given drinking water by gavage and NRG vehicle by tail vein injection, respectively.

4.3 Echocardiography

Before treatment and at the end of the second and third treatment cycles, the rats in each group underwent echocardiography after ketamine anesthesia to measure the changes in cardiac function.

4.4 Hemodynamic measurements

After the third treatment cycle, the rats were anesthetized by intraperitoneal injection of 3% pentobarbital, and a median neck incision was made to isolate the left common carotid artery, intubate, and detect the hemodynamic parameters of the artery and left ventricle.

5. Experimental results

Compared with the negative control group, NRG could significantly improve the hemodynamics of hypertensive rats, in which -dp/dt showed a statistical difference (-7467.6±715.8 and -5488.1±1340.3, respectively, p=0.016); while Cato Puli significantly reduced blood pressure in hypertensive rats (174.5±33.0 vs 216.5±23.2 and 228.0±26.0; p=0.029, p=0.017).

6 Conclusion

rhNRG was administered to hypertensive heart failure rats at a dose of 6.5ug/kg for 5 consecutive days, with 2 days of drug withdrawal as a treatment cycle. After 2 or 3 cycles of treatment, it can prevent left ventricular end-diastolic and end-systolic The volume was further expanded and the hemodynamics was improved, thereby comprehensively improving the cardiac function of the hypertensive heart failure rats. From the data in Table 1, captopril can improve the cardiac function of hypertensive heart failure rats by lowering blood pressure, while rhNRG can increase the rate of left ventricular pressure drop in isovolumic diastolic phase-dp/dt, while Nonhypertensive pathway to improve cardiac function in hypertensive heart failure rats.

Table 1 Hemodynamic parameters of each group after 3 treatment cycles of administration

group MAP -dp/dt negative control 174.7±16.8 -5488.1±1340.3 NRG 182.5±18.8 -7467.6±715.8 Captopli 139.9±24.8 -5441.2±1007.3

Example 2: Study on the effect of recombinant human Nürngin on cardiac function in patients with heart failure with preserved ejection fraction

In order to evaluate the cardiac function effect of recombinant human Nürngin on heart failure patients with preserved ejection fraction, a preliminary clinical experiment was conducted in the Sixth People's Hospital affiliated to Shanghai Jiaotong University, including 2 cases in the placebo group and 2 cases in the experimental group.

1. Main inclusion criteria:

1.1 Left ventricular ejection fraction (LVEF) ≥ 50% (diagnosed by two-dimensional echocardiography);

1.2 New York Heart Function (NYHA) II or III;

1.3 A clear diagnosis of chronic heart failure (including medical history, symptoms, signs), and clinical symptoms have been stable in the past 1 month;

1.4 The target dose or maximum tolerated dose has been reached for at least 1 month after receiving standard treatment drugs for heart failure, or the dose has not been changed within the past 1 month;

1.5 Understand and sign the informed consent.

2. Study drug:

Name: Recombinant human Nürnglin for injection Specifications: 250μg/vial

Dosage form: lyophilized powder for injection

Route of Administration: Intravenous infusion

Placebo (zero dose):

Name: Excipients for Recombinant Human Nürburgring Lyophilisate

Dosage form: lyophilized powder for injection

Route of Administration: Intravenous infusion

3. The route of administration, dosage and course of treatment are shown in Table 2:

Table 2 Dosage, route and course of treatment

4. Data collection: in the screening period, 11-13d and 30d, measure the mitral valve blood flow spectrum of two-dimensional echocardiography.

5. Results and discussion:

Table 3 Numerical changes of IVRT and DT in mitral valve blood flow spectrum

From the results in Table 3, it can be seen that the IVRT and DT values of patients given placebo are gradually increasing; while the patients given NRG, their IVRT and DT values have decreased significantly, showing that their diastolic function has improved to a certain extent.

The above enumerated embodiments do not limit the protection scope of the present invention. Those skilled in the art can make adjustments and changes to the present invention without departing from the spirit and scope of the present invention. Therefore, the protection scope of the present invention should be defined according to the claims, rather than the specific embodiments.

sequence listing

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Claims (10)

1. Use of NRG for the manufacture of a medicament for the prevention, treatment or delay of heart failure with preserved ejection fraction in a mammal.
2. 2. The use of claim 1, wherein the NRG is NRG-1.
3. 3. The use of claim 1, wherein the NRG comprises the amino acid sequence of SEQ ID NO 1.
4. 4. The use of claim 1, wherein the mammal is a human.
5. 5. A pharmaceutical formulation for preventing, treating or delaying heart failure with preserved ejection fraction in a mammal, characterized in that it comprises an effective amount of NRG.
6. 6. The formulation of claim 5, wherein the NRG is NRG-1.
7. 7.The formulation of claim 5, wherein the NRG comprises the amino acid sequence of SEQ ID NO 1.
8. 8. The formulation of claim 5, wherein the mammal is a human.
9. 9. A composition for the prevention, treatment or delay of heart failure with preserved ejection fraction in a mammal, characterized in that it comprises a pharmaceutical preparation according to claim 5 and other drugs for the treatment of heart failure with preserved ejection fraction.
10. 10. A kit for preventing, treating or delaying heart failure with preserved ejection fraction in a mammal comprising the pharmaceutical formulation of claim 5 and instructions for use of the pharmaceutical formulation.